Novel Potent and Selective DPP-4 Inhibitors: Design, Synthesis and Molecular Docking Study of Dihydropyrimidine Phthalimide Hybrids.

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as anti-hyperglycemic agents that improve glycemic control in type 2 diabetic patients, either as monotherapy or in combination with other antidiabetic drugs.

Methods: A novel series of dihydropyrimidine phthalimide hybrids was synthesized and evaluated for their in vitro and in vivo DPP-4 inhibition activity and selectivity using alogliptin as reference. Oral glucose tolerance test was assessed in type 2 diabetic rats after chronic treatment with the synthesized hybrids ± metformin. Cytotoxicity and antioxidant assays were performed. Additionally, molecular docking study with DPP-4 and structure activity relationship of the novel hybrids were also studied.

Results: Among the synthesized hybrids, , , , and had stronger in vitro DPP-4 inhibitory activity than alogliptin. Moreover, an in vivo DPP-4 inhibition assay revealed that and have the strongest and the most extended blood DPP-4 inhibitory activity compared to alogliptin. In type 2 diabetic rats, hybrids , and exhibited better glycemic control than alogliptin, an effect that further supported by metformin combination. Finally, , , and had the highest radical scavenging activity in DPPH assay.

Conclusions: Hybrids , and are potent DPP-4 inhibitors which may be beneficial for T2DM treatment.